Alzheimer's Disease (AD) is a disorder of the later decades of life characterized by dementia. In clinical terms, it consists of a diffuse deterioration of mental function, primarily in thought and memory and secondarily in feeling and conduct. Alzheimer's Disease has been used to designate dementia appearing before the age of 65 years. When the syndrome presents after that age, the term senile dementia of the Alzheimer's type is used. In fact, it appears reasonable to consider both types as representing a single syndrome. The true incidence of the disorder is unknown, although recent data suggest that the incidence of all dementia in the U.S. population may be over 100 cases per 100,000, with its prevalence being over 550 per 100,000. Alzheimer's Disease probably affects at least 30 to 50% of patients with dementia, and in the United States there may be over one million individuals with severe dementia and several million more with mild to moderate dementia. It has been estimated that 1 out of every 6 persons over the age of 65 in the United States suffers form moderate dementia, and a majority of patients in nursing home populations are affected with the disorder. The average age of onset is between 70 and 79 years, but without better information on the population at risk, a more accurate statement is not presently possible. The incidence of the syndrome clearly increases with advancing age. A family history of Alzheimer's Disease is present in 5 to 10% of the patients.
At the present time, the clinical diagnosis of Alzheimer's Disease is one of exclusion. Secondary causes of loss of memory and impaired cognitive function may result from multiple infarcts, leading to so-called multi-infarct dementia, or from intracranial mass lesions such as subdural hematomas, brain tumors, or granulomas. Central nervous system infections of viral and bacterial origin, or even slow vital disorders such as Jakob-Creutzfeldt Disease, are part of the differential diagnosis. Furthermore, metabolic disorders involving vitamin B.sub.12 metabolism, thiamine or folate deficiency, thyroid dysfunction, hepatic and renal failure, as well as drug toxicity may present as dementia. Nevertheless, when all these secondary causes, many of which are reversible, are eliminated, cerebral atrophy of unknown cause or Alzheimer's Disease still covers the largest number of patients. Elevations of aluminum content in brain have been implicated in the pathogenesis of the disorder but appear to be secondary rather than primary.
The pathological picture of Alzheimer's Disease has been well characterized over the years. It consists of senile plaques, which result from degeneration of nerve endings, and neurofibrillary tangles, which represent an alteration in the cytoskeletal apparatus. In addition, intracellular cytoplasmic eosinophilic inclusions, termed Hirano bodies, are present, primarily in the hippocampus. Granulovascular degeneration is also noted. Senile plaques and neurofibrillary tangles in the brain are part of the "normal" aging process. However, at any age, patients with clinical Alzheimer's Disease appear to have a much higher concentration of these abnormalities than do normal individuals.
Paired helical filaments (PHFs) are the principal structural elements of AD neurofibrillary tangles (NFTs) (1). Although not restricted to AD, the number of NFTs correlates with the severity of dementia in AD (1). PHFs also occur in the neurites surrounding amyloid-rich senile plaque (SP) cores, and in neuropil-threads (NTs) that represent altered neuronal processes (1). Low M.sub.r microtubule-associated proteins (MAPs) known as .tau. are major constituents of PHFs (1). A soluble form of PHFs may be formed from .tau. (2). Although other neuronal-cytoskeleton polypeptides also may be components of NFTs and the neurites in SP coronas (1), only peptide sequences from the COOH-terminal third of .tau. have been recovered directly from purified AD PHFs (3). The 60- to 68-kD polypeptides, previously known as A68 and now referred to as PHF.tau., were initially identified with the ALZ50 monoclonal antibody (MAb) and were thought to be AD-specific and present in NFTs (4). Despite immunological and biochemical data that imply that A68 is a modified form of .tau., this hypothesis is controversial, and the mechanism whereby this modification could occur is unknown (5, 6). For example, almost all available antibodies to .tau., including ALZ50, react with A68 (5). Nevertheless, A68 has a higher M.sub.r, a more acidic isoelectric point, and far lower solubility in nonionic detergents than .tau. (7). Hence, the precise relation of A68 to .tau. and to PHFs is unknown.
Accordingly, there remains a need for rapid and accurate methods of detecting Alzheimer's Disease.